PROJECT SUMMARY/ABSTRACT Chlamydia is now the most commonly reported infectious disease in the United States, and more than 3 million new cases occur annually. To date, no Chlamydia vaccine is available. Greater understanding of the adaptive immune response to Chlamydia genital infection will be required if an effective vaccine is to be developed. This project proposes to examine the activation, effector function, and maintenance of memory CD4 T cells in the female reproductive tract (FRT) during Chlamydia reinfection. We recently generated several Chlamydia-specific MHC Class II tetramers, which allow for the first time direct visualization of endogenous, antigen-specific CD4 T cells following Chlamydia FRT infection. Using these unique tools, we specifically propose to: (1) Characterize the antigen-specific memory CD4 T cell responses to Chlamydia muridarum reinfection in the FRT, (2) Identify the major antigen presenting cell population responsible for memory CD4 T cell activation, and (3) Determine whether antigen-persistence and tissue-resident macrophages are required for memory CD4 T cell maintenance. We anticipate that characterization of the temporal and spatial attributes of memory responses to Chlamydia reinfection and evaluation of how immunological memory is maintained in the FRT will provide important insights into the rational design of an urgently needed Chlamydia vaccine.